ES2907611T3 - Crystal forms of (1S,3'R,4'S,5'S,6'R)-6-[(4-ethylphenyl)methyl]-3',4',5',6'-tetrahydro-6'-(hydroxymethyl) spiro[isobenzofuran-1(3H) 2'-[2H]pyran]-3',4',5'-triol - Google Patents

Abstract

A crystal of a compound represented by Formula (XI): **(See formula)** which is i) a monohydrate, ii) a co-crystal with sodium acetate, or iii) a co-crystal with potassium acetate .

Description

DESCRIPTION

Crystal forms of (1S,3'R,4'S,5'S,6'R)-6-[(4-ethylphenyl)methyl]-3',4',5',6-tetrahydro-6-(hydroxymethyl)spiro[ isobenzofuran-1(3H) 2'-[2H]pyran]-3',4',5'-triol

technical field

The present invention relates to a particular spiroketal derivative crystal and a process for its preparation.

prior art

A spiroketal derivative having a certain structure is known to be useful for preventing or treating diabetes (see Patent Documents 1 to 4). For example, WO 2006/080421 A1 (Patent Document 1) describes a compound represented by Formula (A):

[Formula 1]

Patent Document 1 also describes a process for preparing the compound represented by Formula (A). Scheme 3 (page 24 of Patent Document 1) indicates a preparation process, in which a dibromobenzene derivative is treated with an alkyl lithium reagent followed by coupling with a lactone, and after conversion to a tin compound , a coupling reaction is carried out in the presence of a palladium catalyst to provide the desired compound.

Additionally, WO 2007/140191 A2 (Patent Document 2) and the corresponding US Patent Application Publication: US 2007/0275907 A1 (Patent Document 3) describe a preparation process in Scheme 4 (pages 24 and 25 and Figure 4 of Patent Document 2), in which a dihalotoluene derivative is treated with n-BuLi, s-BuLi, t-BuLi, Mg or the like followed by coupling with a lactone, and a tin compound obtained after several steps is subjected to coupling with a benzyl halide derivative to provide the desired compound.

Furthermore, Patent Document 1 discloses a compound represented by Formula (B):

[Formula 2]

stating that the compound has excellent inhibitory activity against SGLT2.

patent documents

Patent Document 1: WO 2006/080421 A1

Patent Document 2: WO 2007/140191 A2

Patent Document 3: US 2007/0275907 A1

Patent Document 4: WO 2008/013280 A1

Summary of the invention

technical problem

As stated above, Scheme 3 in Patent Document 1 and Scheme 4 in Patent Document 2 disclose a scheme for preparing a compound having a spiroketal structure from a dihalobenzene derivative. However, the synthesis method using a tin compound needs complicated operations and necessarily requires a step for carefully removing a tin compound, which may exist as an impurity. Therefore, these processes are not suitable for industrial production. Additionally, these patent documents do not describe any specific examples with respect to the preparation schemes. Actually, an efficient and convenient industrial process for the preparation of the compounds represented by the formulas (A) and (B), which are used as an active ingredient of a medicine, is not known.

In addition, there has been no report regarding the existence of crystals of the compound represented by Formula (B) having excellent inhibitory activity against SGLT2.

An object of the present invention is to provide an efficient and convenient process, which is suitable for industrial production, to prepare spiroketal derivatives used as an active ingredient of a medicament, and to provide a useful synthetic intermediate, and to provide a crystal having excellent properties. properties. in storage stability, ease of handling in the formulation process and the like.

Solution to the problem

The present inventors have carried out intensive studies to achieve the above-mentioned objects, and accordingly have found a method for regioselective metalation of one of multiple halogen atoms in a benzene ring. The present inventors have also found that a coupling reaction proceeds smoothly through a novel organometallic compound as an intermediate, which can be easily prepared. Additionally, the present inventors have found that two consecutive coupling reactions can be carried out as an efficient reaction in a single pot.

The present invention provides a process for preparing a desired spiroketal derivative without using a heavy metal such as tin or an organotransition metal complex in carbon-carbon bond-forming reactions. The process using a heavy metal such as tin or an organotransition metal complex necessarily requires a step for carefully removing these reagents, which may exist as impurities, while the process of the present invention does not need such a step. Therefore, the process is particularly superior as an industrial process for a medicinal substance. Furthermore, the present inventors have found a crystalline form of the compound represented by Formula (I) and a process for preparing the crystalline form. The present inventors have also found that the crystal form has excellent properties as a medicine or medicinal substance.

The present invention relates to a crystal of a compound represented by Formula (XI):

What is it

i) a monohydrate,

ii) a co-crystal with sodium acetate, or

iii) a co-crystal with potassium acetate.

The present invention also relates to a process for preparing the crystal of a compound according to the present invention, wherein the compound is represented by Formula (XI):

where the procedure comprises

Step d): Converting a compound of Formula (XI) to a compound of Formula (Xc):

where P7 is a hydroxy protecting group;

Step e): crystallize the compound of Formula (Xc) and purify the compound by recrystallization;

Step f): Removing (a) protecting group(s) from a compound of Formula (Xc) to provide a compound of Formula (XI) of high purity and crystallizing the resulting compound to provide the crystal of Formula (XI).

A process for preparing a compound represented by Formula (I) is disclosed herein:

[Formula 3]

where n is an integer selected from 0 to 3, m is an integer selected from 0 to 5;

R1 and R2 are independently selected from C1-C10 alkyl optionally substituted by one or more Ra, C3-C10 cycloalkyl optionally substituted by one or more Ra, C2-C10 alkenyl optionally substituted by one or more Ra, C3-C10 cycloalkenyl optionally substituted by one or more Ra, C2-C10 alkynyl optionally substituted with one or more Ra, aryl optionally substituted with one or more Ra, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more Ra, cyano, a halogen atom, nitro, mercapto, -OR3, -NR4R5, -S(O)pR6, -S(O)qNR7R8, -C(=O)R35, -CR36=NOR37, -C(=O)O9, -c(=O)NR10R11 , and -SiR12R13R14; wherein, when n is 2 or more, each of R1 may be the same or different; when m is 2 or more, each of R2 may be the same or different; or two R1 on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a carbocyclic ring or a heterocyclic ring, which are fused to the benzene ring; and two R2 on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a carbocyclic ring or a heterocyclic ring, which are fused to the benzene ring;

p is an integer selected from 0 to 2; q is an integer selected between 1 and 2;

R3 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, aryl, heteroaryl, -SIR12R13R14, or -C(=O)R15;

R4 and R5 are independently selected from hydrogen atom, hydroxy, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, aryl, heteroaryl, -SiR12R13R14, and -C(=O)R15;

R6 is C1-C10 alkyl, C3-C10 cycloalkyl, aryl, or heteroaryl, wherein when p is 0, R6 may additionally be -SiR12R13R14, or -C(=O)R15;

R , R , R and R are independently selected from hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, -SiR12R13R14, and -C(=O)R15;

R9 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, or -SiR12R13R14;

Ra are independently selected from C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, aryl, heteroaryl, hydroxy, halogen atom, -NR21R2, -O38, -SR26, -S(O)2R27 ,

- SiR23R24R25, carboxy, -C(O)NR28R29, -C(=O)R30, -CR31=NOR32, cyano and -S(O)rNR33R34;

r is an integer selected between 1 and 2;

R12, R13, R14, R23, R24 and R25 are independently selected from C1-C10 alkyl and aryl;

R15 and R30 are independently selected from hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 alkylamino, C1-C10 dialkylamino, C1-C10 alkylthio, aryl and heteroaryl;

R , R , R , R , R and R are independently selected from hydrogen atom, hydroxy, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, aryl, heteroaryl, -SiR23R24R25, and -C(=O )R30;

R26 is a hydrogen atom, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyloxy, aryloxy, C3-C10 cycloalkyl, aryl, heteroaryl, -C(=O)R30, or -SiR23R24R25;

R27 is hydroxy, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, -SiR23R24R25, or -C(=O)R30;

R31 is a hydrogen atom, C1-C10 alkyl, or C3-C10 cycloalkyl;

R32 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl, -SiR23R24R25, or -C(=O)R30;

R35 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, C1-C10 alkylthio, aryl, or heteroaryl;

R36 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, or C2-C10 alkynyl;

R37 is a hydrogen atom, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, aryl, heteroaryl, -SiR12R13R14, or -C(=O)R15; Y

R38 is C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C3-C10 cycloalkenyl, C2-C10 alkynyl, (C1-C10)alkylthio, aryl, heteroaryl, -SiR23R24R25, or -C(=O)R30 ;

comprising:

Step a): treating a compound of Formula (II):

[Formula 4]

wherein X1 and X2 are independently selected from a bromine atom or an iodine atom;

P1 is a metal ion, a hydrogen atom or a hydroxy protecting group;

R41 is a group defined as R1, where the group may have one or more protecting groups; and n is defined as before;

with an organometallic reagent, and then reacted with a compound of Formula (III):

wherein P2, P3, P4, and P5 are independently selected from a hydroxy protecting group; or P2 and P3, P3 and P4, and P4 and P5 together may independently represent a divalent group to protect two hydroxy groups and form a ring; to obtain a compound represented by Formula (IVa):

[Formula 6]

definen como antes; y X es un ion hidrógeno;where

define as before; and X is a hydrogen ion;

Step b): treating a compound represented by Formula (IVb):

[Formula 7]

organometallic, and then reacting with a compound represented by Formula (V):

[Formula 8]

where R42 is a group defined as R2, where the group may have one or more protecting groups, and m

is defined as before; Y

which may additionally comprise one or more steps to introduce a protecting group and/or remove a protecting group, in the steps defined above, or in any step before or after any of the steps defined above.

In one example, the aforementioned method further comprises:

Step c): subjecting a compound represented by Formula (VI):

[Formula 9]

where R41, R42, m, n, p1, P2, P3, P4, P5, and P6 are as defined above; to the following two stages:

Step (1): treating a compound represented by Formula (VI), wherein P1 is a hydrogen atom, under acidic conditions, with the proviso that when P1 is a protecting group, the step further comprises a deprotection step before of the treatment; Y

Step (2): remove a hydroxy group, which is formed in Step b), by reduction reaction; with the proviso that any of the two stages can be carried out first; to obtain a compound represented by Formula (VII):

[Formula 10]

where R41, R42, m, n, P2, P3, P4, and P5 are defined as above.

The term "a halogen atom" referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The term "C1-C10 alkyl" means a straight or branched alkyl group having 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, I-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl , n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropylmethyl, cyclohexylmethyl and the like. C1-C10 alkyl further includes straight or branched C1-C6 alkyl and C1-C4 alkyl.

The term "C3-C10 cycloalkyl" means a cyclic alkyl group having 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, and the like. C3-C10 Cycloalkyl further includes C3-C8 cycloalkyl and C3-C7 cycloalkyl.

The term "C2-C10 alkenyl" means a straight or branched alkenyl group having 2 to 10 carbon atoms. Examples include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), propen-2-yl, 3-butenyl (homoallyl), 1,4-pentadien-3-yl, and the like C2-C10 alkenyl further includes a linear or branched C2-C6 alkenyl and C2-C4 alkenyl.

The term "C3-C10 cycloalkenyl" means a cyclic alkenyl group having 3 to 10 carbon atoms. Examples include cyclopentenyl, cyclohexenyl, and the like. C3-C10 cycloalkenyl further includes C5-C10 cycloalkenyl and the like.

The term "C2-C10 alkynyl" means a straight or branched alkynyl group having 2 to 10 carbon atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, and the like. C2-C10 alkynyl further includes straight or branched C2-C6 alkynyl and C2-C4 alkynyl.

The term "C1-C10 alkoxy" means an alkyloxy group having a linear or branched alkyl group having 1 to 10 carbon atoms as an alkyl radical. Examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n -hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, 2-ethylbutoxy and the like. C1-C10 Alkoxy further includes straight or branched C1-C6 alkoxy and C1-C4 alkoxy.

The term "(C1-C10)alkylamino" means an alkylamino group having a linear or branched alkyl group having 1 to 10 carbon atoms as an alkyl radical. Examples include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino and the like C1-C10 alkylamino further includes C1-C6 alkylamino and a linear or branched (C1-C4)alkylamino.

The term "di(C1-C10)alkylamino" means a dialkylamino group having straight or branched alkyl groups each having 1 to 10 carbon atoms as two alkyl moieties. The two alkyl radicals may be the same or different. Examples include dimethylamino, diethylamino, di(n-propyl)amino, di(i-propyl)amino, di(n-butyl)amino, di(s-butyl)amino, di(i-butyl)amino, di(t-butyl) )amino, ethyl(methyl)amino, methyl(n-propyl)amino, methyl(ipropyl)amino, n-butyl(methyl)amino, s-butyl(methyl)amino, I-butyl(methyl)amino, t-butyl (methyl)amino and the like. (C1-C10)alkylamino further includes a linear or branched di(C1-C6)alkylamino and di(C1-C4)alkylamino.

The term "(C1-C6)alkylthio" means an alkylthio group having a straight or branched alkyl group having 1 to 10 carbon atoms as an alkyl radical. Examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio and the like C1-C10 alkylthio further includes C1-C6 alkylthio and C1-C6 alkylthio (C1-C4)thio linear or branched.

The term "saturated, partially unsaturated, or unsaturated heterocyclyl" referred to herein means, for example, a saturated, partially unsaturated, or unsaturated 4- to 10-membered heterocyclic group containing one or more heteroatoms selected from an atom of nitrogen, an oxygen atom and a sulfur atom. Examples of the heterocyclyl include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl, morpholinyl, and the like.

The term "aryl" is not particularly limited, but means an aryl group having an aromatic hydrocarbon ring with 6 to 14 carbon atoms, for example, 6 to 10 carbon atoms. Examples include phenyl, 1-naphthyl, 2-naphthyl, and the like.

The term "heteroaryl" is not particularly limited, but means a 4- to 10-membered aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples of the heteroaryl include pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and the like.

The term "a carbocyclic ring" referred to herein is not particularly limited, but means a hydrocarbon ring having 6 to 14 carbon atoms, for example, 6 to 10 carbon atoms. Examples include benzene, naphthalene, and the like.

The term "a heterocyclic ring" as referred to herein is not particularly limited, but means a 4- to 10-membered heterocyclic ring containing one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the heterocyclic ring include pyridine, pyrimidine, pyrazine, triazine, quinoline, quinoxaline, quinazoline, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, and the like.

When the group defined as R1 and R2 has one or more protectable groups such as hydroxy, carboxy, carbonyl, amino and mercapto, the group may be protected by a protecting group. The selection of a protecting group introduced into each group and the operations for the introduction and removal of a protecting group can be carried out, for example, as described by Greene and Wuts, in "Protective Groups in Organic Synthesis", (4th edition, John Wiley & Sons, 2006).

Examples of the protecting group for a hydroxy group, which may be contained in R1 and/or R2, include C1-C10 alkyl optionally substituted with one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more R52, alkenyl C2-C10, -Si(R53)3, -C(=O)R54, -B(O55)2 and the like;

wherein R51 is independently selected from aryl optionally substituted with one or more R56, C1-C10 alkoxy optionally substituted with one or more aryl, C1-C10 alkylthio and arylselenyl groups;

R52 is independently selected from C1-C10 alkoxy;

R53 and R55 are independently selected from C1-C10 alkyl and aryl;

R54 is a hydrogen atom, C1-C10 alkyl, aryl optionally substituted with one or more C1-C10 alkoxy groups, heteroaryl, amino optionally substituted with one or more R57, C1-C10 alkoxy optionally substituted with one or more aryl groups, or aryloxy optionally substituted with one or more nitro groups;

R56 is independently selected from C1-C10 alkyl, C1-C10 alkoxy, aryl, and heteroaryl;

R57 is independently selected from C1-C10 alkyl and aryl.

Preferred examples of a hydroxy protecting group include methyl, benzyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, t-butyl, allyl, vinyl, triphenylmethyl (trityl), trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl, isobutyryl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, and the like.

Examples of a protecting group for an amino group, which may be contained in R1 and/or R2, include C1-C10 alkyl optionally substituted with one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more R52, C2-C10 alkenyl, -Si(R53)3, -C(=O)R54, and the like; where R51, R52, R53 and R54 are as defined above. Preferred examples of an amino group protecting group include benzyl. Additionally, a primary amino group can be protected by converting it to a phthalimido group or a succinimido group.

Examples of a protecting group for a carboxy group, which may be contained in R1 and/or R2, include an ester-forming group 1oTO such as C1-C10 alk 1-yl optionally substituted with one or more R51, alk 1u C2-C10 CeQni ClQo, -Si(R )3, where R and R are defined as above; and an amide-forming group such as -NR R , wherein R58 and R59 are independently selected from C1-C10 alkyl optionally substituted with one or more R51, C2-C10 alkenyl and -Si(R53)3 and R51 and R53 are defined like before. Preferred examples of conversion by introducing a protecting group to carboxy include ethyl ester, benzyl ester and t-butyl ester.

The group formed by the introduction of one or more protecting groups in the group defined as R1 and R2 is included within the definitions of R41 and R42

R1 and R2 are not particularly limited, but are independently selected from, for example, C1-C10 alkyl optionally substituted with one or more Ra, C3-C10 cycloalkyl optionally substituted with one or more Ra, C2-C10 alkenyl optionally substituted with one or more Ra. or more Ra, C3-C10 cycloalkenyl optionally substituted with one or more Ra, C2-C10 alkynyl optionally substituted with one or more Ra, aryl optionally substituted with one or more Ra, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more Ra, and -SiR R R . More preferably R and R are independently selected from C1-C6 Alkyl, C3-C6 Cycloalkyl, aryl and -SiR12R13R14. When n or m is 0, R1 or R2 do not exist respectively on the benzene ring. In one example, n is 0, m is 0 or 1, and R2 is C1-C4 alkyl.

The halogen atom defined as R1 and R2 is preferably a fluorine atom or a chlorine atom.

The metal ion defined in P1, P6 and X means a metal ion, which may be a counterion of an alkoxide ion. Examples thereof include alkali metal ion and alkaline earth metal ion such as lithium ion, sodium ion, potassium ion, cesium ion and magnesium ion. The metal ion can form a complex with another metal. Examples of the metal ion also include a metal ion formed by reacting an organometallic reagent used herein with a hydroxy group (for example, a lithium ion).

The hydroxy-protecting group included in the definitions of P1 to P6 is not limited as long as it is commonly used as a hydroxy-protecting group. A protecting group can be selected and introduced to a hydroxy group as described by Greene and Wuts, in "Protective Groups in Organic Synthesis" (4th edition, John Wiley & Sons, 2006). Examples thereof include C1-C10 alkyl optionally substituted by one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted by one or more R52, C2-C10 alkenyl, -Si(R53)3, -C(=O )R54, -B(O55)2 and the like.

The term "a divalent group to protect two hydroxy groups and to form a ring" referred to herein means a divalent group connecting two oxygen atoms of two hydroxy groups such as a C1-C10 alkylene group (for example, methylene, methylmethylene, dimethylmethylene), carbonyl group and the like. The organometallic reagent used herein is not limited as long as it is suitable for a metal-halogen exchange reaction on a benzene ring. Examples include C1-C10 alkyllithium (eg, n-butyllithium, s-butyllithium, t-butyllithium), aryllithium (eg, phenyllithium, naphthyllithium, dimethoxyphenyllithium), alkyl( C1-C10)magnesium (eg, n-butylmagnesium chloride, isopropylmagnesium chloride), di(C1-C10)alkylmagnesium (eg, di(n-butyl)magnesium), and the like. The organometallic reagent can be used in the presence of an inorganic salt or an organic salt (for example, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium triflate, magnesium chloride, magnesium bromide, lithium triflate). magnesium), or it can be used as a mixture with the inorganic salt or the organic salt. Examples of the organometallic reagent also include, for example, a mixture or reaction product of magnesium compounds and organolithium compounds described on pages 11 to 17 of WO 2001/057046; a mixture or a reaction product of butyl magnesium chloride and butyl lithium; isopropylmagnesium bromide and butyl lithium; isopropylmagnesium bromide and lithium chloride; dibutylmagnesium and butyllithium; dibutylmagnesium and ethoxylithium; dibutylmagnesium and t-butoxylithium; dibutylmagnesium lithium hexamethyldisilazide; butyl magnesium bromide and butyl lithium; isopropylmagnesium bromide, butyl lithium and lithium chloride; butylmagnesium chloride, butyllithium and ethoxylithium; butylmagnesium chloride, butyl lithium and lithium hexamethyldisilazide; isopropylmagnesium bromide, butyl lithium and ethoxylithium; zinc chloride and butyl lithium, diethyl zinc and butyl lithium; and organozinc complex described in JP 2004-292328 A.

For example, in Steps a) and b), n-butyl lithium is used as the organometallic reagent. Also, a metal complex formed by the sequential reaction of two or more organometallic reagents can be used as the organometallic reagent. For example, after treating a compound represented by Formula (II) with butyl lithium, butyl magnesium chloride and butyl lithium may be added to the reaction system followed by reaction with a compound represented by Formula (III).

The substituted silyl group defined herein by the formulas -SiR12R13R14, -SiR23R24R25, -Si(R53)3 and the like is not particularly limited. Examples thereof include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl, and the like.

In a compound represented by Formula (II) used in Step a), both X1 and X2 are, for example, an atom of bromine Examples of P1 include a lithium ion, a hydrogen atom, and a protecting group such as (C1-C6)alkoxyC1-C6alkyl (eg, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl) , C1-C6 arylmethyloxyalkyl (for example, benzyloxymethyl), tetrahydropyranyl, a -Si(R53)3 group (for example, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl), aralkyl (for example, benzyl, 4- methoxybenzyl, trityl), a group -B(O55)2 and the like.

In step a), treatment of a compound represented by Formula (II) with an organometallic reagent can be carried out in a solvent that is suitable for a metal-halogen exchange reaction. Examples of the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane), hydrocarbons (for example, pentane, hexane, heptane, benzene , toluene), N,N-tetramethylethylenediamine, N,N-tetramethylpropanediamine and a mixed solvent of two or more solvents listed above. When P1 is a metal ion or a protecting group, an organometallic reagent may be used in an amount of 0.5 to 1.5 equivalents, for example, 0.8 to 1.1 equivalents. When P1 is a hydrogen atom, an organometallic reagent may be used in an amount of 1.5 to 3.0 equivalents, for example, 1.8 to 2.2 equivalents.

From the standpoint of improving regioselectivity, an organometallic reagent may be added in portions. For example, an organometallic reagent may be added for 15 minutes or more, preferably 15 to 300 minutes, more preferably 30 to 300 minutes. Additionally, the reagent may be added intermittently and the above noted addition time may include one or more interruptions. For example, an organometallic reagent may be added in two or three portions with one or two interruptions, eg, each for 5 to 300 minutes, preferably 15 to 120 minutes.

Also, from the viewpoint of improving regioselectivity, after completing the addition of an organometallic reagent, an aryl halide can be added to the reaction mixture in a certain amount, for example, 0.05 to 0. 0.5 equivalents, preferably 0.1 to 0.4 equivalents, relative to the amount originally included in the reaction mixture. Examples of the aryl halide include iodobenzene, diiodotoluene, dibromotoluene, the reaction substrate (eg, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene), and the like. Preferably, the reaction substrate can be used as an aryl halide.

From the viewpoint of improving regioselectivity, an organometallic reagent may be added, for example, at a temperature of -80 to 30°C, preferably -60 to 25°C, particularly -15 to 0°C, in portions (eg dropwise) to the reaction system. After the addition of the reagent, the reaction mixture can be stirred at a suitable temperature (for example, -80 to 0°C, preferably -15 to 0°C) for a certain period of time (for example, from 0.1 to 5 hours) to complete the reaction.

From the viewpoint of improving regioselectivity, when P1 is a metal ion or a protecting group, an organometallic reagent may be added in an amount of less than 1 equivalent, for example 0.4 to 0.9 equivalents, preferably 0.8 equivalents, and then the reaction mixture may be stirred at a suitable temperature, for example -80 to 30°C, preferably -60 to 25°C, particularly -15 to 0°C, for a certain period of time, for example 0.1 to 5 hours, preferably 0.5 to 2 hours. After that, an organometallic reagent may be added in an amount of, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, and then the reaction mixture may be stirred at a temperature of, for example , -80 to 30°C, preferably -60 to 25°C, particularly -15 to 0°C, for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours. The equivalent numbers given above mean a molar equivalent relative to a compound represented by Formula (II) used as a reactive substrate. It should be noted that the term "equivalent" refers to "molar equivalent" in the specification, unless otherwise specified.

From the viewpoint of improving regioselectivity, when P1 is a hydrogen atom, an organometallic reagent may be added in an amount of less than 2 equivalents, for example 1.4 to 1.9 equivalents, preferably 1, 8 equivalents and then the reaction mixture can be stirred at a suitable temperature, for example -80 to 30°C, preferably -60 to 25°C, particularly -15 to 0°C, for a certain period of time. time, for example 0.1 to 5 hours, preferably 0.5 to 2 hours. After that, an organometallic reagent may be added in an amount of, for example, 0.1 to 0.7 equivalents, preferably 0.3 equivalents, and then the reaction mixture may be stirred at a temperature of, for example , -80 to 30°C, preferably -60 to 25°C, particularly -15 to 0°C, for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours. The equivalent numbers given above mean a molar equivalent relative to a compound represented by Formula (II) used as a reactive substrate.

In the reaction of Step a), a halogen-metal exchange reaction occurs preferably in X1 of the compound of Formula (II), which has several reactive sites in the molecule and, consequently, the reaction provides more of the compound of Formula (IVa) than that of a by-product provided by a halogen-metal exchange reaction at X2. In this regard, the reaction of Step a) is a regioselective reaction. The regioselectivity of the reaction in Step a) is not particularly limited. However, the ratio of desired compound:by-product in the reaction of Step a) is, for example, 10:1 or more, preferably 30:1 or more.

After a metal-halogen exchange reaction using C1-C10 alkyllithium (for example, n-butyllithium, sbutyllithium, or t-butyllithium), aryllithium (for example, phenyllithium, naphthyllithium, dimethoxyphenyllithium ), another organometallic reagent (for example, n-butyl-magnesium chloride and n-butyl lithium, or dibutylmagnesium) can be added, and then the reaction mixture can be stirred at an appropriate temperature of, for example, -80 at 30°C, preferably -60 to 25°C, particularly -15 to 0°C, for a certain period of time, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours for form a complex.

In one example, a compound represented by Formula (II), where P1 is a hydrogen atom, is used in step a).

In a compound represented by Formula (III) used in Step a), examples of P2, P3, P4, and P5 include a protecting group such as (C1-C6)alkoxyC1-C6alkyl (for example, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-methoxy-1-methylethyl), arylmethyloxyC1-C6alkyl (for example, benzyloxymethyl), tetrahydropyranyl, a group:

-Si(R53)3 (eg trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, t-butyldiphenylsilyl), aralkyl (eg benzyl, 4-methoxybenzyl, triphenylmethyl), a group: -B(O55)2, alkyl (C1-C6)carbonyl (eg acetyl, propionyl, pivaloyl), (C1-C6)alkoxycarbonyl (eg methoxycarbonyl, isopropyloxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl), t-butyl. Additionally, P4 and P5 together may represent a divalent group to protect two hydroxy groups and form a ring (eg -CH2-, -CH(CH3)-, -C(CH3)2-, -CHPh-).

A reaction of a compound of Formula (II), which is treated with an organometallic reagent, with a compound of Formula (III) may be carried out, for example, by adding a solution of a compound of Formula (II) in a solvent portionwise (eg dropwise) to a reaction mixture containing a compound of Formula (III) (eg 1.0 to 1.1 equivalents) at an appropriate temperature of eg -100 at 0°C, preferably -90 to -30°C, particularly -80 to -40°C. Examples of a suitable solvent include ethers (eg, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane), hydrocarbons (eg, hexane, heptane, benzene , toluene) and the like, and a mixture of two or more solvents mentioned above. After the addition of a compound of Formula (II), the reaction can be completed by stirring for a certain period of time (for example, 0.5 to 5 hours), at an appropriate temperature of, for example, -80 to -40°C

A conventional procedure for working up the reaction can be used. The resulting product can be purified by conventional procedure to provide a compound of Formula (IVa). From the viewpoint of simplifying production processes, reducing the amount of solvents used, and production costs, it is preferred that the following step is carried out without a preparation process for this reaction.

The process may include a step of introducing a protecting group into a compound of Formula (IVa) to obtain a compound of Formula (IVb), where P6 is a hydroxy protecting group. The introduction of a protecting group in the step can be carried out, for example, after the addition of a compound of Formula (II) previously treated with an organometallic reagent to a compound of Formula (III), a reagent for introducing a protecting group ( eg 1.0 to 2.0 equivalents) to the reaction mixture, if necessary together with a suitable amount (eg 0.1 to 1.0 equivalents) of a base, eg triethylamine, N-methylmorpholine, ethyldiisopropylamine and the like, at an appropriate temperature of, for example, -100 to 0°C, preferably -90 to -60°C, particularly 80 to -75°C. After the addition of the reagent, the reaction can be completed by stirring for a certain period of time (for example, 0.1 to 5 hours) at the same temperature or at an elevated temperature.

Examples of a reagent for introducing a protecting group include a silylation reagent such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride and t-butyldiphenylsilyl chloride; an alkyl halide such as methyl iodide and benzyl bromide; an acid halide such as pivaloyl chloride; a C1-C6 alkoxy(C1-C6)alkyl halide such as methoxymethyl chloride and ethoxymethyl chloride; and the like. When P1 of a compound of Formula (IVa) is a metal ion or hydrogen atom, a protecting group can be introduced at the site to obtain a compound of Formula (IVb) wherein P1 is a hydroxy protecting group using an amount of the reagent at this stage. Therefore, in one example, a compound of Formula (IVb) is used in Step b) wherein P6 is a hydroxy protecting group. A conventional procedure for treating the reaction can be used to introduce a protecting group. The resulting product can be purified by conventional procedure to provide a compound of Formula (IVb). From the viewpoint of simplifying production processes, reducing the amount of solvents used and production costs, it is also preferred that the following step is carried out without a preparation process for this reaction.

The treatment of a compound of Formula (IVb) with an organometallic reagent in Step b) can be carried out carried out using a suitable solvent for a halogen-metal exchange reaction. Examples of the solvent include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane), hydrocarbons (for example, pentane, hexane, heptane, benzene, toluene ) and the like, and a mixture of two or more solvents mentioned above. When no preparation process is carried out in the previous step, a solvent used in the previous step can be used.

An organometallic reagent may be used in an amount of 0.3 to 4.0 equivalents, for example, 1.0 to 3.0 equivalents, preferably 1.1 to 2.1 equivalents.

The organometallic reagent can be added to the reaction system in portions (for example, dropwise) at a temperature of, for example, -100 to 30°C, preferably -90 to -10°C, particularly -90 to -70°C After the addition of an organometallic reagent, the reaction can be stirred for a certain period of time of, for example, 0.1 to 5 hours, preferably 0.5 to 2 hours at an appropriate temperature of, for example, - 100 to 30°C, preferably -90 to -10°C, particularly -90 to -70°C.

A reaction of a compound of Formula (IVb), which is treated with an organometallic reagent, with a compound of Formula (V) may be carried out, for example, by adding a solution of a compound of Formula (V) in a solvent appropriate, at an appropriate temperature of, for example, -100 to 30°C, preferably -90 to -10°C, particularly -80 to -70°C, to a reaction mixture containing a compound of Formula ( IVb). In this connection, a compound of Formula (V) can be used in an amount of 1.0 to 15.0 equivalents, for example, 1.0 to 5.0 equivalents, preferably 1.1 to 2.2 equivalents. . Examples of a suitable solvent include, for example, ethers (eg, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane), hydrocarbons (eg, pentane , hexane, heptane, benzene, toluene) and the like, and a mixture of two or more solvents mentioned above. After the addition of Formula (V), the reaction can be completed by stirring for a certain period of time, for example, 0.1 to 5 hours at an appropriate temperature of, for example, -90 to 0°C.

A conventional procedure can be used in working up the reaction in Step b). The resulting product can be purified by a conventional procedure to obtain a compound of Formula (VI). From the viewpoint of simplifying production processes, reducing the amount of solvents used, and production costs, it is preferred that the following step is carried out without a preparation process for this reaction.

The compound of Formula (VI), wherein P1 is a hydroxy protecting group is converted to a compound wherein P1 is a hydrogen atom by carrying out deprotection before Step (1) in Step c). In one example, protecting groups introduced as P2 to P6 are also removed by deprotection. Deprotection can be carried out by a method well known in the art, for example, using an acid or Lewis acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, ptoluenesulfonic acid, boron trifluoride complex diethyl ether, boron trichloride and boron tribromide; a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium carbonate; an organometallic reagent such as butyl lithium and Grignard reagent; a metal hydride reagent such as lithium aluminum hydride, lithium borohydride and diisobutylaluminum hydride; a combined reagent of a Lewis acid and a nucleophile such as boron trifluoride-diethyl ether complex and ethanethiol, aluminum halide and sodium iodide, aluminum halide and a thiol, and aluminum halide and a sulfide; or by hydrogenation using a catalyst such as palladium on carbon, platinum, a homogeneous complex of palladium, a homogeneous complex of ruthenium and a homogeneous complex of rhodium.

A spiro ring structure is formed by treatment in Step (1). The reaction of Step (1) can be carried out in an appropriate solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, acetone, acetic acid ester (for example, ethyl acetate, methyl acetate, isopropyl acetate, and the like), methylene chloride, chloroform, dichloroethane, water, or a mixture of two or more of the above-mentioned solvents at a suitable temperature eg -20 to 100°C, preferably 0 to 80°C, particularly 20 to 30°C. The reaction time can be appropriately adjusted, for example, from about 0.5 to 15 hours, preferably from about 2 to 10 hours. The acid used is not particularly limited, but a Lewis acid can be used. Specific examples thereof include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, boron trichloride and boron tribromide.

In one example, the removal of protecting groups introduced as P1 to P6 and the formation of a spiro ring can be carried out at the same time by treatment under acidic conditions in Step (1).

A reduction reaction in Step (2) of Step c) can be carried out in an appropriate solvent such as tetrahydrofuran (THF), methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, acetic acid ester (for example, ethyl acetate, methyl acetate, isopropyl acetate), acetone, water or a mixture of two or more solvents mentioned above at a suitable temperature of, for example, -80 to 80°C, preferably -30 at 70°C, particularly -20 to 60°C. The reaction time can be set appropriately, for example, 0.5 to 24 hours, preferably about 5 to 15 hours. The reduction reaction is not particularly limited, but the reaction can be carried out using a reducing reagent and/or a suitable catalyst to remove a hydroxy group on a carbon atom connecting two benzene rings in a compound of Formula ( SAW). Examples of the reducing reagent and the catalyst include a metal catalyst under a hydrogen atmosphere (for example, palladium on carbon, platinum, a homogeneous complex of palladium, a homogeneous complex of ruthenium, a homogeneous complex of rhodium); a hydride reducing reagent combined with a Lewis acid (eg, aluminum chloride and sodium borohydride, trifluoroacetic acid, and triethylsilane).

In one example, the removal of one or more protecting groups introduced as P1 and P6 and the removal of the hydroxy group can be carried out simultaneously by the reduction reaction in Step (2). Either Step (1) or (2) may be carried out first in Step c). The deprotection of P1 or P1 to P6 can be carried out at any step prior to Step (1).

The process may further comprise a step to remove any protecting groups included in a compound obtained in Step c). The process may also comprise a step of converting a compound of Formula (I) obtained by the process to another compound of Formula (I).

In one example, Steps a) and b) can be carried out in a one pot reaction. That is, the steps can be carried out by adding the necessary reagents in order without applying any preparation or purification procedures. Therefore, the process is advantageous in that the process can be carried out in a one-pot reaction to achieve simplification of production steps, reduction in the amount of solvents used and production costs, as well as because a desired compound can be obtained in excellent yield.

Further described herein is a process for preparing a high purity compound represented by Formula (I) defined hereinabove, comprising:

Step d): Converting a compound of Formula (I) to a compound of Formula (X):

[Formula 11]

where R41, R42, m and n are defined as above, and P7 is a hydroxy protecting group;

Step e): crystallize the compound of Formula (X) and purify the compound by recrystallization;

Step f): Removing one or more protecting groups from a compound of Formula (X) to provide a compound of Formula (I) of high purity. A particular version of this method, which is as defined in claim 12, is in accordance with the present invention.

Examples of a compound of Formula (X) set forth above include compounds of formulas (Xa) and (Xb):

[Formula 12]

The hydroxy protecting group defined as P7 is not particularly limited as long as it is commonly used to protect a hydroxy group. Examples thereof include protecting groups described by Greene and Wuts, in "Protective Groups in Organic Synthesis" (4th edition, John Wiley & Sons 2006). Examples of a hydroxy protecting group also include C1-C10 alkyl optionally substituted by one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted by one or more R52, C2-C10 alkenyl, -Si(R53)3, - C(=O)R54, -B(O55)2, where R51 to R55 are as defined above.

In one embodiment of the present invention, P7 is selected from (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and -SiR23R24R25, wherein R23, R24 and R25 are as defined above.

The reaction to introduce a protecting group in Step d) can be carried out in a manner well known in the art related to the present invention. For example, the reagent and reaction conditions described by Greene and Wuts, in "Protective Groups in Organic Synthesis" (4th edition, John Wiley & Sons 2006) can be used in the reaction. Examples of solvents used in the reaction include ethers (for example, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, t-butylmethyl ether, diisopropyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane), hydrocarbons (for example, benzene, toluene ), acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetone, acetic acid ester (for example, ethyl acetate, methyl acetate, isopropyl acetate), methylene chloride, chloroform, dichloroethane , water and a mixture of two or more solvents mentioned above.

The reagent used to introduce a protecting group can be selected based on the protecting group to be introduced. For example, C1-C6 alkylcarbonyl chloride, C1-C6 alkoxycarbonyl chloride, Cl-SiR23R24R25 and the like can be used in an amount of 1.0 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents with respect to the hydroxy group. If necessary, a base can be used. Examples of the base include triethylamine, pyridine, N,N-dimethylaniline, 4-(dimethylamino)pyridine, imidazole, 1-methylimidazole, ethyldiisopropylamine, lutidine, morpholine, potassium carbonate, sodium carbonate, and sodium hydrogencarbonate. Preferably, 1-methylimidazole can be used. The reaction temperature is not particularly limited, but the reaction can be carried out at a temperature of, for example, -20 to 50°C, preferably -10 to 25°C, for a certain period of time, for example, 1 to 10 hours, preferably 2 to 4 hours.

Crystallization in Step e) can be carried out using an appropriate solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butylmethyl ether, cyclopentylmethyl ether, 1,2- dimethoxyethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene, or water, or a mixture of two or more of the aforementioned solvents. Also the recrystallization in the step can be carried out in a manner well known in the art pertaining to the present invention using an appropriate solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, ethyl acetate, isopropyl acetate, tetrahydrofuran, t-butylmethyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane, diisopropyl ether, acetonitrile, acetone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, heptane, toluene, or water, or a mixture of two or more solvents listed above.

Deprotection can be carried out by selecting a method known in the art pertaining to the present invention, which is suitable for removing the protecting group. For example, the reagent and reaction conditions described by Greene and Wuts, in "Protective Groups in Organic Synthesis" (4th edition, John Wiley & Sons 2006) can be used. For example, the deprotection can be carried out using an acid or Lewis acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride-diethyl ether complex, boron trichloride and boron tribromide. boron; a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium carbonate; an organometallic reagent such as butyl lithium and Grignard reagent; a metal hydride reagent such as lithium aluminum hydride, lithium borohydride and diisobutylaluminum hydride; a combined reagent of a Lewis acid and a nucleophile such as diethyl ether complex of boron trifluoride and ethanethiol, aluminum halide and sodium iodide, aluminum halide and a thiol, and aluminum halide and a sulfide; or by hydrogenation using a catalyst such as palladium on carbon, platinum, a homogeneous complex of palladium, a homogeneous complex of ruthenium and a homogeneous complex of rhodium and the like.

In one example, the crude product obtained in a process comprising Steps a) to c) defined herein is used as a compound of Formula (I) in Step d). In a process comprising Steps a) to c) defined above, a desired product can be produced without purification. Therefore, from the viewpoint of improving production efficiency, it is advantageous to combine the process comprising Steps a) to c) with Steps d) to f) in which high purification can be carried out. . Likewise, steps d) to f) may be combined with another procedure to prepare a compound of Formula (I). In the present invention, the term "high purity" means improved purity compared to a compound of Formula (I) used as the starting material of Step d). Examples of a high purity compound of Formula (I) include a compound of Formula (I) having a purity of 90.0% by weight or more, preferably from 97.0% by weight or more.

In one example, the process further comprises a step to crystallize a high purity Formula (I) compound obtained in step f). The solvent used for crystallization is, for example, a solvent selected from water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and 1-hexanol; ethers such as tetrahydrofuran, t-butylmethyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane, and diisopropyl ether; esters such as ethyl acetate, propyl acetate, and hexyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and N,N-dibutylformamide; halogenated hydrocarbons such as 1-chlorohexane; hydrocarbons such as n-propylbenzene, hexylbenzene, heptane, and toluene; ketones such as acetone, 2-butanone, and 2-heptanone; acetonitrile; and dimethyl sulfoxide; or a mixture of two or more solvents mentioned above.

The resulting compound of Formula (I) can be further purified by recrystallization. The solvent used for recrystallization is a solvent selected from water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and 1-hexanol; ethers such as tetrahydrofuran, t-butylmethyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane, and diisopropyl ether; esters such as ethyl acetate, propyl acetate, and hexyl acetate; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and N,N-dibutylformamide; halogenated hydrocarbons such as 1-chlorohexane; hydrocarbons such as n-propylbenzene, hexylbenzene, heptane, and toluene; ketones such as acetone, 2-butanone, and 2-heptanone; acetonitrile; and dimethyl sulfoxide; or a mixture of two or more solvents mentioned above.

either

In another example, a high purity compound of Formula (I) is produced wherein n is 0, m is 0 or 1, and R is alkyl

C1-C4. In another example, a crystal of a compound of Formula (I) of high purity is produced in which n is 0, m is

0 or 1 and R2 is C1-C4 alkyl.

The process comprising steps d) to f) enables a compound of Formula (I) to be prepared in high purity without a purification process requiring complicated operations and a large amount of solvents and absorbents, such as column chromatography. Therefore, the process is advantageous from the standpoint of improving production efficiency and reducing production costs. The method of removing impurities from a compound used as a drug is very important, and therefore the procedure is useful for the stable supply of safe drugs.

It should be understood that the above information regarding the process is also applicable to the process of the present invention, to the extent that it does not contradict the requirements of claim 12.

Also disclosed herein is a compound represented by Formula (IVb):

[Formula 13]

where R41, n, X2, define as above. The compound is useful c for a compound of Formula

Also disclosed is a compound of Formula (VI):

[Formula 14]

where R41, R42, m, n, p1, P2, P3, P4, P5, and P6 are defined as above. The compound is also useful as a synthetic intermediate for a compound of Formula (I).

According to the present invention, there is provided a crystal of a compound of Formula (XI):

[Formula 15]

which is i) a monohydrate, ii) a co-crystal with sodium acetate, or iii) a co-crystal with potassium acetate.

In one embodiment of the present invention, the crystal is a monohydrate. Herein, the monohydrate is not particularly limited as long as the crystal stably maintains a humidity in an amount of about 1 equivalent under conditions (for example, temperature, relative humidity, and the like) in which drugs are used or stored. Commonly. In one embodiment of this aspect, the crystal is provided as a co-crystal with sodium acetate or potassium acetate. In another embodiment of the present invention, a monohydrate crystal of a compound of Formula (XI) of high purity is provided.

The monohydrate crystal of the present invention is characterized by having peaks at diffraction angles (20) of approximately 3.5°, 6.9° and 13.8°; specifically, about 3.5°, 6.9°, 13.8°, 16.0°, 17.2°, and 18.4°; more specifically, approximately 3.5°, 6.9°, 10.4°, 13.8°, 16.0°, 17.2°, 18.4°, 20.8°, 21.4°, and 24 .4° in the X-ray powder diffraction pattern. The co-crystal with sodium acetate of the present invention is characterized by having peaks at diffraction angles (20) of approximately 4.9°, 14.7°, 16.0°, 17.1° and 19.6° ; more specifically about 4.9°, 8.7°, 9.3°, 11.9°, 12.9°, 14.7°, 16.0°, 17.1°, 17.7°, 19 .6°, 21.6° and 22.0° in the X-ray powder diffraction pattern. The co-crystal with potassium acetate of the present invention is characterized by having peaks at diffraction angles (20) of approximately 5.0°, 15.1°, 19.0°, 20.1° and 25.2° ; more specifically, approximately 5.0°, 10.0°, 10.4°, 12.4°, 14.5°, 15.1°, 19.0°, 20.1°, 21.4° and 25 .2° in the X-ray powder diffraction pattern. Herein, the powder X-ray diffraction pattern can be measured in a common method. With respect to the diffraction angle values of the X-ray powder diffraction peaks of the crystal of the present invention, some errors (for example, about ±0.2) may be observed by the measurement conditions and state of measurement. the samples.

The monohydrate crystal of the present invention can be obtained by crystallization from a solvent selected from water or a mixture of methanol and water, ethanol and water, acetone and water, or 1,2-dimethoxyethane and water. For example, crystallization can be carried out using a mixture of acetone and water where the mixing ratio is preferably acetone:water=1:3.5 to 1:7 by volume, more preferably acetone:water=1:4. at 1:7 by volume.

The sodium acetate co-crystal of the present invention can be obtained by crystallization from a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, propyl acetate, hexyl acetate, 2-butanone, 2- heptanone, n-propylbenzene, hexylbenzene and 1-chlorohexane, or a mixture of two or more solvents mentioned above, preferably a mixture of methanol and isopropanol.

The co-crystal with potassium acetate of the present invention can be obtained by crystallization from a solvent selected from methanol, isopropanol, 1-hexanol, acetonitrile, ethyl acetate, N,N-dibutylformamide, acetone and diisopropyl ether, or a mixture of two or more solvents mentioned above, preferably of a mixture of methanol and isopropanol.

The monohydrate crystal of the present invention has the property that the moisture content remains substantially constant under a certain relative humidity range and the compound is easy to handle in the formulation process. Additionally, the monohydrate crystal and co-crystals with sodium acetate and potassium acetate of the present invention are useful for preparing a pharmaceutical formulation having excellent storage stability. On the other hand, the monohydrate crystal and co-crystals with sodium acetate and potassium acetate can be used to efficiently and highly purify a compound of Formula (XI), and therefore the crystal is also useful from the point of view of view of the effective preparation of a medicament containing the compound.

Brief description of the drawings

Figure 1 shows an example of the measurement results of the water adsorption isotherm measured in Test Example 1.

Fig. 2 shows an example of measurement results of X-ray powder diffraction of monohydrate crystal measured in Test Example 5 (Condition 1).

Fig. 3 shows an example of measurement results of X-ray powder diffraction of monohydrate crystal measured in Test Example 5 (Condition 2).

Figure 4 shows an example of powder X-ray diffraction measurement results of the amorphous form measured in Test Example 5.

Figure 5 shows an example of X-ray powder diffraction measurement results of the sodium acetate co-crystal measured in Test Example 5.

Figure 6 shows an example of X-ray powder diffraction measurement results of the potassium acetate co-crystal measured in Test Example 5.

Description of achievements

examples

Preferred examples of the present invention will now be described in more detail. However, the present invention will not be limited to these examples.

NMR analysis was carried out with a nuclear magnetic resonance apparatus: JNM-ECP-500 or JNM-ECP-400 (manufactured by JOEL). Mass spectral analysis was carried out with a mass spectrometer: LCT Premier x E (manufactured by Waters). Preparative high performance liquid chromatography was carried out with the GL-Science preparative isolation system. High performance liquid chromatography was carried out with Agilent 1100 (manufactured by Agilent). Moisture analysis was carried out with a KF analysis apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation). When the resulting product was used in the next step without purification, a portion of the product or another product separately prepared in the same manner was appropriately purified for NMR measurement.

[Example 1] Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose

Step 1: Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

[Formula 16]

EITHER

Q X s\OTMS

tmso^ X v X otms

SMTO

To a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) was added trimethylsilyl chloride (29.1 kg ) at 40°C or less, and then the mixture was stirred at 30°C to 40°C for 2 hours. After the mixture was cooled to 0°C, toluene (34 kg) and water (39 kg) were added. The organic layer was separated and washed with 5% sodium dihydrogen phosphate aqueous solution (39.56 kg x 2) and water (39 kg x 1). The solvent was evaporated under reduced pressure to give the title compound as an oil. The product was used in the next step without further purification.

1 H NMR (sCDCl) 5: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74-3.83 (3H, m), 3.90 (1H, t, J=8.0 Hz ), 3.99 (1H, d, J=8.0 Hz), 4.17 (1H, dt, J=2, 5, 8.0Hz).

Step 2: Synthesis of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene

[Formula 17]

Under nitrogen atmosphere, to a solution of 2,4-dibromobenzyl alcohol (40 g, 0.15 mol) in tetrahydrofuran (300 ml) was added 2-methoxypropene (144 ml, 1.5 mol) at room temperature and then , the mixture was cooled to 0°C. At the same temperature, p-toluenesulfonic acid in pyridinium (75 mg, 0.30 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate cooled to 0°C and extracted with toluene. The organic layer was washed with a saturated aqueous chloride solution. sodium sulfate, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to give the title compound as an oil in quantitative yield. The product was used in the next step without further purification.

1 H NMR (CDCls) 5: 1.44 (6H, s), 3.22 (3H, s), 4.48 (2H, s), 7.42 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J=1.5, 8.0 Hz), 7.68 (1H, d, J=1.5 Hz).

Step 3: Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran

[Formula 18]

Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (70 g, 207 mmol), obtained in the previous step, was dissolved in toluene (700 mL) and added t-butylmethyl ether (70 mL) and n-butyl lithium in hexane (1.65 M, 138 mL, 227 mmol) dropwise at 0°C over 30 min. After stirring the mixture for 1.5 hours at 0°C, the mixture was added dropwise to a solution of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol) in tetrahydrofuran (507 ml) at -78°C, and the reaction mixture was stirred for 2 hours at the same temperature. Triethylamine (5.8 mL, 41 mmol) and trimethylsilyl chloride (29.6 mL, 232 mmol) were added, and the mixture was warmed to 0°C and stirred for 1 hour to give a solution containing 2, 3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran. The resulting solution was cooled to -78°C and n-butyl lithium in hexane (1.65M, 263 mL, 434 mmol) was added dropwise at the same temperature. After stirring the mixture at -78°C for 30 minutes, 4-ethylbenzaldehyde (62 mL, 455 mmol) was added dropwise at -78°C, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the organic layer was separated and washed with water. The solvent was evaporated under reduced pressure to give a product containing the title compound as an oil (238g). The product was used in the next step without further purification. A portion of the oil was purified by HPLC (column: Inertsil ODS-3, 20 mm I.D. * 250 mm; acetonitrile, 30 mL/min) to provide four diastereomers of the title compound (two mixtures, each with two diastereomers).

Mixture of diastereomers 1 and 2:

1 H NMR (500 MHz, CDCls) 5: -0.47 (4.8H, s), -0.40 (4.2H, s), -0.003-0.004 (5H, m), 0.07-0, 08 (13H, m), 0.15-0.17 (18H, m), 1.200 and 1.202 (3H, each t, J=8.0Hz), 1.393 and 1.399 (3H, each s), 1.44 (3H, s), 2.61 (2H, q, J=8.0Hz), 3.221 and 3.223 (3H, each s), 3.43 (1H, t, J=8.5 Hz), 3, 54 (1H, dd, J=8.5, 3.0 Hz), 3.61-3.66 (1H, m), 3.80-3.85 (3H, m), 4.56 and 4, 58 (1H, each d, J=12.4 Hz), 4.92 and 4.93 (1H, each d, J=12.4 Hz), 5.80 and 5.82 (1H, each d, J=3.0 Hz), 7.14 (2H, d, J= 8.0 Hz), 7.28-7.35 (3H, m), 7.50-7.57 (2H, m ).

MS (ESI+): 875 [M+Na]+.

Mixture of diastereomers 3 and 4:

1 H NMR (500 MHz, toluene-da, 80°C) 5: -0.25 (4H, s), -0.22 (5H, s), 0.13 (5H, s), 0.16 (4H , s), 0.211 and 0.214 (9H, each s), 0.25 (9H,s), 0.29 (9H,s), 1.21 (3H, t, J=7.5 Hz), 1 .43 (3H, s), 1.45 (3H, s), 2.49 (2H, q, J=7.5 Hz), 3.192 and 3.194 (3H, each s), 3.91-4, 04 (4H, m), 4.33-4.39 (2H, m), 4.93 (1H, d, J=14.5Hz), 5.10-5.17 (1H, m), 5, 64 and 5.66 (1H, each s), 7.03 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.59-7.64 ( 1H, m), 7.87-7.89 (1H, m).

MS (ESI+): 875 [M+Na]+.

Step 4: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-B-D-glucopyranose

Under a nitrogen atmosphere, the oil containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl )tetrahydropyran (238 g), which was obtained in the previous step, was dissolved in acetonitrile (693 ml). Water (37 mL) and 1N aqueous HCl (2.0 mL) were added and the mixture was stirred at room temperature for 5.5 hours. Water (693 ml) and n-heptane (693 ml) were added to the reaction mixture and the aqueous layer was separated. The aqueous layer was washed with n-heptane (693 ml x 2), and the water was evaporated under reduced pressure to give a product containing water and the title compound (a mixture of diastereoisomers) as an oil (187 g). The product was used in the next step without further purification.

1H NMR (500 MHz, CD3OD) 5: 1.200 (3H, t, J=7.7Hz), 1.201 (3H, t, J=7.7Hz), 2.61 (2H, q, J=7.7Hz) , 3.44-3.48 (1H, m), 3.63-3.68 (1H, m), 3.76-3.84 (4H, m), 5.09 (1H, d, J= 12.8 Hz), 5.15 (1H, d, J=12.8 Hz), 5.79 (1H, s), 7.15 ( 2H, d, J=7.7 Hz), 7.24 and 7.25 (1H, each d, J=8.4 Hz), 7.28 (2H, d, J=7.7 Hz), 7.36 (1H, d, J=8.4, 1 0.5 Hz), 7.40-7.42 (1H, m).

MS (ESI+): 425 [M+Na]+.

Step 5: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl1-3-D-glucopyranose (crude product)

[Formula 20]

To a solution of the oil containing 1,1-anhydro-1 -C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose (187 g), which was obtained in the previous step , in 1,2-dimethoxyethane (693 mL) was added 5% Pd/C (26 g, 6.2 mmol, water content ratio: 53%), and the mixture was stirred under hydrogen gas at room temperature for 4 hours. After filtration, the filtrate was evaporated under reduced pressure to give an oil containing the title compound (59g). The purity of the resulting product was 85.7%, which was calculated based on the area ratio measured by HPLC. The product was used in the next step without further purification.

1 H NMR (CD3OD) 5: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m ), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (3H, m).

MS (ESI+): 387 [M+1]+.

HPLC measurement conditions:

Column: Cadenza CD-C1850 mm P/NCD032

Mobile phase: Eluent A: H2O, Eluent B: MeCN

Gradient operation: Eluent B: 5% to 100% (6 min), 100% (2 min)

Flow rate: 1.0ml/min

Temperature: 35.0°C

Detection wavelength: 210nm

Step 6: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-B,D-glucopyranose

[Formula 21]

Under a nitrogen atmosphere, to a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose (59 g) and 4- (dimethylamino)pyridine (175 g, 1436 mmol) was added dropwise to methyl chloroformate (95 mL, 1231 mmol) at 0°C in acetonitrile (1040 mL). The mixture was allowed to warm to room temperature while stirring for 3 hours. After addition of water, the mixture was extracted with isopropyl acetate. The organic layer was washed with 3% potassium hydrogen sulfate aqueous solution and 20% sodium chloride (three times) and 20% sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. at reduced pressure. Ethanol (943 mL) was added to the resulting residue, and the mixture was heated to 75°C to dissolve the residue. The mixture was cooled to 60°C and a seed crystal of the title compound was added to it. The mixture was cooled to room temperature and stirred for 1 hour. After observing solid precipitation, water (472 mL) was added and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the title compound (94 g). To the product (91 g) was added ethanol (1092 ml), and the product was dissolved by heating to 75°C. The solution was cooled to 60°C and a seed crystal of the title compound was added to it. The mixture was cooled to room temperature and stirred for 1 hour. After observing solid precipitation, water (360 mL) was added and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the title compound [83 g, total yield of 2,4-dibromo-1-( 1-methoxy-1-methylethoxymethyl)benzene used in Step 3: 68%].

1 H NMR (CDCls) 5: 1.20 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 3.50 (3H, s), 3, 76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J=2.5, 11, 8Hz), 4.33 (1H, dd, J=4.5, 12.0Hz), 4.36-4.40 (1H, m), 5.11-5.20 (3H, m), 5.41 (1H, d, J=10.0 Hz), 5.51 (1H, t, J=10.0 Hz), 7.07-7.11 (4H, m), 7.14 (1H , d, J=7.5 Hz), 7.19 (1H, dd, J=1.5, 7.8 Hz), 7.31 (1H, d, J=1.5 Hz).

MS (ESI+): 619 [M+1]+, 636 [M+18]+.

Another preparation was carried out in the same manner as in Step 6, except that a seed crystal was not used, to give the title compound as a crystal.

Step 7: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-B-D-glucopyranose

[Formula 22]

To a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-pD-glucopyranose ( 8.92 kg wet powder, corresponding to 8.00 kg dry powder) in 1,2-dimethoxyethane (28 kg) sodium hydroxide solution (4 mol/L, 30.02 kg) was added to 20°C, and the mixture was stirred for 1 hour. Water (8.0 kg) was added to the mixture and the layers were separated. To the organic layer, 25% sodium chloride aqueous solution (40 kg) and ethyl acetate (36 kg) were added. The organic layer was separated, washed with 25% sodium chloride aqueous solution (40 kg), and the solvent was evaporated under reduced pressure. The purity of the resulting residue was 98.7%, which was calculated based on the area ratio measured by HPLC. To the resulting residue, acetone (32.0 kg) and water (0.8 kg) were added, and the solvent was evaporated under reduced pressure. To the resulting residue, acetone (11.7 kg) and water (15.8 kg) were added, and the solution was cooled to 5°C or less. Water (64 kg) was added to the solution at 10°C or less, and the mixture was stirred at the same temperature for 1 hour. The resulting crystal was collected by centrifugation and washed with a mixture of acetone (1.3 kg) and water (8.0 kg). The resulting wet powder was dried by ventilation under the conditions of air temperature of 13 to 16°C and relative humidity of 24% to 33% for 8 hours, to give a monohydrate crystal (water content: 4.502%) of the compound of the title (3.94kg). The purity of the resulting compound was 99.1%, which was calculated based on the area ratio measured by HPLC.

1 H NMR (CD3OD) 5: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m ), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (3H, m).

MS (ESI+): 387 [M+1]+.

HPLC measurement conditions:

Column: Capcell pack ODS UG-120 (4.6 mm I.D. x 150 mm, 3 ^m, manufactured by Shiseido Co., Ltd.) Mobile phase: Eluent A: H2O, Eluent B: MeCN

Mobile phase delivery: The concentration gradient was controlled by mixing Eluent A and Eluent B as indicated in the following table.

Table 1

Flow rate: 1.0ml/min

Temperature: 25.0°C

Detection wavelength: 220nm

Method for measuring water content:

Analysis method: coulometric titration method

KF Analysis Apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation)

Anode solution: Aquamicron AX (manufactured by Mitsubishi Chemical Corporation)

Cathode solution: Aquamicron CXU (manufactured by Mitsubishi Chemical Corporation)

[Example 2] Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran

[Formula 23]

According to the procedure of Example 1, Step 3, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene was treated with n-butyllithium in hexane, 3,4,5-tris(trimethylsilyloxy) -6-trimethylsilyloxymethyl-tetrahydropyran-2-one, triethylamine and trimethylsilyl chloride. The reaction mixture was subjected to a preparative procedure and the resulting residue was purified by HPLC (column; Inertsil ODS-3, 20 mm I.D. x 250 mm; acetonitrile, 30 mL/min) to provide the title compound as two diastereoisomers. isolated.

Diastereomer 5:

1 H NMR (500 MHz, CDCls) 5: -0.30 (9H, s), 0.095 (9H, s), 0.099 (9H, s), 0.16 (9H, s), 0.17 (9H, s ), 1.41 (3H, s), 1.43 (3H, s), 3.20 (3H, s), 3.37-3.44 (2H, m), 3.62 (1H, dd, J=10.5, 7.5 Hz), 3.81-3.89 (3H, m), 4.62 (1H, d, J= 13.2 Hz), 4.81 (1H, d, J =13.2 Hz), 7.38 (1H, d, J=8.8, 2.5 Hz), 7.46 (1H, d, J=8.8 Hz), 7.70 (1H, d , J= 2.5 Hz).

MS(ESI+): 819[M+Na]+.

Diastereomer 6:

1 H NMR (500 MHz, toluene-da, 80°C) 5: -0.16 (9H, s), 0.18 (9H, s), 0.22 (9H, s), 0.23 (9H, s), 0.29 (9H, s), 1.405 (3H, s), 1.412 (3H, s), 3.16 (3H, s), 3.87 (1H, dd, J=10.5, 4 .3 Hz), 3.98 (1H, dd, J=4.3, 1.5 Hz), 4.02 (1H, dd, J= 10.5, 2.5Hz), 4.14 (1H, s), 4.26 (1H, s wide), 4.38 (1H, s wide), 4.90-4.96 (2H, m), 7.34 (1H, dd, J=8.5, 1.5Hz), 7.70 (1H, d, J=8.5 Hz), 7.97 (1H, s, wide s).

MS (ESI+): 819 [M+Na]+.

[Example 3] Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-pivaloyl-p-D- glucopyranose

[Formula 24]

To a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose monohydrate (3.95 g, 9.77 mmol) and 4 -(dimethylamino)pyridine (8.36 g, 68.4 mmol) in dichloromethane (40 mL) was added dropwise to pivaloyl chloride (7.8 mL, 63.5 mmol) under ice-bath cooling and the mixture was stirred at room temperature for about 24 hours. Water was added and the resulting mixture was extracted with hexane. The organic layer was washed sequentially with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 150 g, hexane:ethyl acetate = 20:1 to 10:1) to give an oily material (7.74 g). The oily material (500mg) was dissolved in isopropanol (4ml). Water (1.5 ml) and isopropanol (1 ml) were added sequentially at room temperature and the mixture was stirred for 1 hour. Water (0.5 ml) was added and the mixture was stirred for a further 1 hour. Further, the mixture was stirred at 0°C for 1 hour and the precipitated crystal was collected by filtration, washed with a mixture of water and isopropanol (1:1, 4 ml) and dried to give the title compound (403 mg).

1 H NMR (CDCls) 5: 0.71 (9H, s), 1.11 (9H, s), 1.17 (9H, s), 1.20 (9H, s), 1.20 (3H, t , J=7.5 Hz), 2.60 (2H, q, J =7.5 Hz), 3.93 (2H, s), 4.09 (1H, dd, J=4.0, 12, 5 Hz), 4.16 (1H, dd, J=2.0, 12.5 Hz), 4.37 (1H, ddd, J=2.0, 4.0, 10.0 Hz), 5, 12 (1H, d, J=12.2 Hz), 5.21 (1H, d, J=12.2 Hz), 5.37 (1H, t, J=10.0 Hz), 5.57 ( 1H,d,J=10.0Hz), 5.69 (1H,t,J=10.0Hz), 7.07 (2H,d,J=8.2Hz), 7.10 (2H, d, J=8.2 Hz), 7.11 (1H, d, J=8.0 Hz), 7.17 (1H, dd, J=1.2, 8.0 Hz), 7.25 ( 1H, s wide).

MS (ESI+): 723 [M+1]+.

[Example 4] Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

To a solution of D-(+)-glucono-1,5-lactone (21.6 kg) and N-methylmorpholine (98.2 kg) in tetrahydrofuran (192 kg) was added trimethylsilyl chloride (79.1 kg ) at 40°C or less, and then the mixture was stirred at 30°C to 40°C for 4 hours. After the mixture was cooled to 17°C, toluene (93.6 kg) and water (109 kg) were added. The organic layer was separated and washed with 5% sodium dihydrogen phosphate aqueous solution (108 kg x 2) and water (108 kg x 1). The solvent was evaporated under reduced pressure. Tetrahydrofuran (154 kg) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (154 kg) was added again and evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (253 kg) to give a solution of the title compound in tetrahydrofuran. The purity of the product was 99.0% (conversion rate: 99.1%), which was calculated based on the area ratio measured by HPLC.

HPLC measurement conditions:

Column: YMC-Pack ODS-AM 4.6mm I.D.*150mm, 3^m (YMC)

Mobile phase: Eluent A: AcONH42 mM/H2O,

Eluent B: 50% (v/v) MeCN/MeOH

Gradient operation: Eluent B: 50% to 95% (15 min), 95% (15 min), 95% to 100% (5 min) and 100% (15 min)

Flow rate: 1.0ml/min

Column temperature: 40°C

Detection wavelength: 200nm

[Example 5] Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl1-p-D-glucopyranose

Step 1: Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran

[Formula 26]

Under argon, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (277 g, 820 mmol) was dissolved in toluene (2616 mL) and t-butylmethyl ether (262 mL) was added dropwise. mL) and n-butyl lithium in hexane (1.54 M, 426 mL, 656 mmol) at -10°C. After stirring the mixture for 0.5 hour at -10°C, n-butyl lithium in hexane (1.54M, 160 mL, 246 mmol) was added dropwise at -10°C. After stirring the mixture for 1 hour at -10°C, to confirm the regioselectivity of the metal-halogen exchange reaction, a small portion of the reaction mixture was taken and added to a saturated aqueous ammonium chloride solution. The ratio of 4-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene and 2-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene included in the resulting mixture was 53:1 (conversion ratio : 98%), which was calculated based on the area ratio measured by HPLC.

After the reaction mixture was cooled to -48°C, the mixture was added dropwise to a solution of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one (402 g, 862 mmol) in tetrahydrofuran (2012 ml) at -77°C, and the reaction mixture was stirred at -70°C for 1.5 hours. Triethylamine (24 mL, 172 mmol) and trimethylsilyl chloride (98 g, 903 mmol) were added, and the mixture was warmed to 0°C to give a solution containing 2,3,4,5-tetrakis(trimethylsilyloxy) -6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)-tetrahydropyran. The resulting solution was cooled to -78°C and n-butyllithium in hexane (1.54M, 1119 mL, 1724 mmol) was added dropwise at the same temperature. After the mixture was stirred for 1 hour, 4-ethylbenzaldehyde (242 g, 1806 mmol) was added dropwise at -78°C, and the mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into 20% ammonium chloride aqueous solution, and the organic layer was separated and washed with water. The solvent was evaporated under reduced pressure to give a product containing the title compound as an oil (879g). The product was used in the next step without further purification. HPLC measurement conditions:

Column: Ascentis Express C18, 3.0mm I.D.*100mm, 2.7^m (Supelco)

Mobile phase: Eluent A: AcONH42 mM/H2O,

Eluent B: MeCN

Gradient operation: Eluent B: 30% to 98% (25 min), 98% (5 min)

Flow rate: 1.0ml/min

Column temperature: 40°C

Detection wavelength: 210nm

Step 2: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl1phenyl1-3-D-glucopyranose

Under a nitrogen atmosphere, the oil containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl )tetrahydropyran (628 g), which was a portion of the product obtained in the previous step, was dissolved in tetrahydrofuran (991 ml). Water (63 mL) and 1N aqueous HCl (23 mL) were added and the mixture was stirred at 28°C for 7 hours. Triethylamine (3.8 ml, 25.8 mmol) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Water (198 ml) and 1,2-dimethoxyethane (396 ml) were added to the residue and the two layers were separated. The aqueous layer was washed with n-heptane (595 ml). Water (99 ml) and 1,2-dimethoxyethane (198 ml) were added to the aqueous phase. The mixture was washed with n-heptane (595 ml), and the aqueous layer was concentrated under reduced pressure. To the resulting residue was added 1,2-dimethoxyethane (793 ml), and the solvent was evaporated under reduced pressure to give an oil containing the title compound (247 g). The product was used in the next step without further purification.

Step 3: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl1-3-D-glucopyranose

[Formula 28]

To a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose (125 g), which was a portion of the product obtained in the above step, in 1,2-dimethoxyethane (400 ml) was added water (150 ml) and 5% Pd/C (19 g, 4.5 mmol, water content ratio: 50%), and the mixture was stirred under an atmosphere of hydrogen gas at room temperature for 6 hours.

The reaction mixture was filtered and the residue was washed with a mixture of 1,2-dimethoxyethane (250 ml) and water (250 ml). The filtrate and washings were combined and 1,2-dimethoxyethane (500 mL) was added. The mixture was washed with nheptane (1000 ml x 2). Ethyl acetate (500 ml) and 25% sodium chloride aqueous solution (600 g) were added to the aqueous layer, and the product was extracted into the organic layer. The separated organic layer was washed with 15% sodium chloride aqueous solution (600 g), and the solvent was evaporated under reduced pressure. Acetone (500 ml) was added to the resulting residue, and the solvent was evaporated under reduced pressure to give the product containing the title compound (106 g). The purity of the resulting product was 93.9%, which was calculated based on the area ratio measured by HPLC. The product was used in the next step without further purification.

HPLC measurement conditions:

Column: Atlantis dC18, 4.6 mm I.D. * 75mm, 3^m (Waters)

Mobile phase: Eluent A: H2O,

Eluent B: MeCN

Gradient operation: Eluent B: 2% to 20% (3 min), 20% to 28% (5 min), 28% (12 min), Eluent B: 28% to 100% (7 min) and 100% ( 8 minutes)

Flow rate: 1.2ml/min

Column temperature: 35°C

Detection wavelength: 210nm

Step 4: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl1-2,3,4,6-tetra-O-methoxycarbonyl-3-D- glucopyranose

[Formula 29]

1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-pD-glucopyranose (106 g), which was obtained in the previous step, and 1-methylimidazole ( 318 mL, 3994 mmol) were dissolved in acetone (400 mL). Under a nitrogen atmosphere, methyl chloroformate (182 mL, 2367 mmol) was added dropwise to the solution at 15°C. The mixture was allowed to warm to 18°C while stirring for 3 hours. After addition of water (800 ml), the mixture was extracted with ethyl acetate (800 ml). The organic layer was washed with 10% potassium hydrogen sulfate aqueous solution and 5% sodium chloride aqueous solution (800 mL), and 20% sodium chloride aqueous solution (800 mL x 2), and then evaporated the solvent under reduced pressure. Ethanol (1200 ml), t-butylmethyl ether (200 ml) and 2-propanol (130 ml) were added to the resulting residue. The mixture was heated to 74°C to dissolve the residue, then cooled to 55°C and stirred for 1 hour. After observing the precipitation of the solid, the mixture was cooled from 55 to 25°C for 1.5 hours. To this was added 2-propanol (270 ml) and the mixture was stirred at 25°C for 1 hour. The resulting crystal was collected by filtration, washed with a mixture of ethanol and 2-propanol (3:1.300 ml) followed by a mixture of ethanol and water (1:1.300 ml) to give the title compound as wet powder. [122 g, corresponding to 104 g dry powder, total yield from 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene used in Step 1: 57%].

Step 5: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-B-D-glucopyranose

[Formula 30]

Under a nitrogen atmosphere, to a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl -p-D-glucopyranose (96 g wet powder, corresponding to 82 g dry powder) in 1,2-dimethoxyethane (328 ml) was added dropwise to aqueous sodium hydroxide solution (4N, 265 ml, 1060 mmol) at 40°C. The mixture was stirred at the same temperature for 4.5 hours. Water (82 ml) was added to the mixture and the organic phase was separated. The organic layer was washed with an aqueous solution of 18% sodium dihydrogen phosphate dihydrate and 12% sodium hydrogen phosphate dodecahydrate (410 ml), and then ethyl acetate (410 ml) was added thereto. The organic layer was washed with 25% sodium chloride aqueous solution (410 ml x 2), and the solvent was evaporated under reduced pressure. To the resulting residue, acetone (410 ml) and water (8.2 ml) were added, and the solvent was evaporated under reduced pressure. To the resulting residue, acetone (164 ml) and water (655 ml) were added, and the residue was dissolved by heating to 28°C. The solution was cooled to 25°C and a seed crystal of the title compound (82mg) was added. The mixture was cooled to 25°C to 20°C over 24 minutes and stirred at 20°C for 1 hour. After observing solid precipitation, the mixture was heated to 25°C and stirred at the same temperature for 1 hour. Subsequently, the mixture was cooled from 25°C to -5°C for 2.4 hours, and the resulting crystals were collected by filtration. Water (246 ml) was added to the resulting crystal, and the mixture was stirred at 4°C for 1 hour. After filtration, the resulting wet powder was dried under reduced pressure (pressure: 1 hPa, outdoor temperature: 20 to 25°C) for 20 minutes to give wet powder (water content: 8.249%). The resulting powder was further dried under reduced pressure (pressure: 25 hPa, outside temperature: 20 to 25°C) for 30 minutes to give the title compound as a monohydrate crystal (44 g, yield 82%, water content 4,470%). The purity of the resulting compound was 99.9%, which was calculated based on the area ratio measured by HPLC.

Method for measuring water content:

Analysis method: coulometric titration method

KF Analysis Apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation)

Anode solution: Aquamicron AX (manufactured by Mitsubishi Chemical Corporation)

Cathode solution: Aquamicron CXU (manufactured by Mitsubishi Chemical Corporation)

The seed crystal used in Example 5, Step 5, was a portion of the crystal obtained in the following procedure.

1,1-Anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose (180.4 g) was dissolved in water (250 ml) and acetone (250 ml). ) at 25°C and insoluble matter was removed by filtration. A mixture of water (326 ml) and acetone (326 ml) was added to the filtrate, and the solution was cooled to 4°C. Water (2.311) was added while stirring the mixture and keeping it at 11°C or less, and the precipitation of the solid was observed. The precipitate was collected by filtration, washed with a mixture of water (289 ml) and acetone (59 ml), and dried by ventilation to give a crystal (160.7 g).

HPLC measurement conditions:

Column: ZORBAX Eclipse XDB-C18, 4.6 mm I.D. *50mm, 1.8^m (Agilent)

Mobile phase: Eluent A: H2O,

Eluent B: MeOH

Gradient operation: Eluent B: 40% to 60% (11.5 min), 60% to 80% (7 min), 80% to 95% (4 min), 95% (5 min)

Flow rate: 1.0ml/min

Column temperature: 50°C

Detection wavelength: 220nm

[Example 6] Halogen-metal exchange reaction in 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene Halogen-metal exchange reactions were carried out in 2,4-dibromo-1-( 1-methoxy-1-methylethoxymethyl)benzene under the following conditions (Conditions 1 to 4). Regioselectivity in the reactions was confirmed by 1H-NMR Analysis.

Condition 1: Under nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (500 mg, 1.48 mmol) was dissolved in toluene (3.65 mL) and t-butylmethyl ether (0 .35ml). To the solution was added n-butyllithium in hexane (1.6M, 1.01 mL, 1.62 mmol) dropwise at 0°C over 3 minutes. After the addition was complete, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a product containing 4-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene and 2-bromo-1-(1-methoxy-1-methylethoxymethyl)benzene, which can be referred to as 4-bromide and 2-bromide respectively hereinafter, in the form of oil (376 mg). Based on 1H NMR analysis of the product, the ratio of 4-bromide:2-bromide was determined to be 16:1, which was calculated based on the integration ratio of the proton peaks at the benzyl position (4 -bromide: 84.43 ppm, 2-bromide: 84.55 ppm).

4-Bromo-1-(1-methoxy-1-methylethoxymethyl)benzene:

1 H NMR (CDCla) 8: 1.41 (6H, s), 3.24 (3H, s), 4.43 (2H, s), 7.21-7.24 (2H, m), 7.44 -7.47 (2H, m).

2-Bromo-1-(1-methoxy¡-1-methylethoxymethyl)benzene:

1 H NMR (CDCla) 8: 1.46 (6H, s), 3.24 (3H, s), 4.55 (2H, s), 7.10-7.14 (1H, m), 7.29 -7.33 (1H, m), 7.51-7.55 (2H, m). Condition 2: Under nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (500 mg, 1.48 mmol) was dissolved in toluene (3.65 mL) and t-butylmethyl ether (0 .35ml). To the solution was added n-butyllithium in hexane (1.6M, 1.01 mL, 1.62 mmol) dropwise at 0°C over 3 minutes. A solution of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (150 mg, 0.44 mmol) in toluene (1.1 mL) and ether t-butylmethyl (0.11 mL). After the addition was complete, the reaction mixture was stirred at 0°C for 30 minutes. To this was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a product containing 4-bromide and 2-bromide as an oil (458 mg). According to 1 H NMR analysis of the product, the ratio of 4-bromide:2-bromide was determined to be 220:1, which was calculated based on the integration ratio of the proton peaks at the benzyl position.

Condition 3: Under nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (150 mg, 0.44 mmol) was dissolved in toluene (1.1 mL) and t-butylmethyl ether (0.11ml). To the solution was added n-butyllithium in hexane (1.6M, 0.3 mL, 0.48 mmol) dropwise at 0°C over 3 minutes. After the addition was complete, the reaction mixture was stirred at 0°C for 30 minutes. To this was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a product containing 4-bromide and 2-bromide as an oil (108 mg). According to 1H NMR analysis of the product, the ratio of 4-bromide:2-bromide was determined to be 16:1, which was calculated based on the integration ratio of the proton peaks at the benzyl position.

Condition 4: Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (500 mg, 1.48 mmol) was dissolved in toluene (3.65 mL) and t-butylmethyl ether (0 .35ml). n-Butyllithium in hexane (1.6M, 1.01 mL, 1.62 mmol) was added dropwise to the solution at 0°C over 30 minutes. After the addition was complete, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a product containing 4-bromide and 2-bromide as an oil (373 mg). According to 1 H NMR analysis of the product, the ratio of 4-bromide:2-bromide was determined to be 40:1, which was calculated based on the integration ratio of the proton peaks at the benzyl position.

[Example 7] Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose

to a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-pD-glucopyranose (88.2 g in wet powder form) in 1,2-dimethoxyethane (285 ml) was added to sodium hydroxide solution (5 M, 285 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After adding an aqueous solution of sulfuric acid (1M, 713 ml) to the mixture, water (100 ml) was added thereto, and the mixture was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with a saturated aqueous sodium chloride solution (1000 ml), dried over anhydrous sodium sulfate (250 g), and about half of the solvent was removed under reduced pressure. The resulting precipitate was collected by filtration and the product was obtained as a crystalline powder (10.3 g). A portion of the product (4mg) was dissolved in dimethylsulfoxide (0.02ml). The solution was lyophilized at -20°C for 2 days to remove dimethylsulfoxide. Water (0.02 ml) was added to the resulting residue, and a very small portion of the product obtained above as a seed crystal was added thereto. The mixture was shaken at 100 rpm with DO ^u B ^l E SHAKE ^r NR-3 (TAITEC) at room temperature for 10 days to give crystallized title compound. The resulting crystal is confirmed to be a monohydrate by X-ray powder diffraction measurement, in which peaks were observed at the same diffraction angles (20) as those of the X-ray powder diffraction pattern of the measured monohydrate. in Test Example 5.

[Example 8] Preparation of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose co-crystal with sodium acetate

1,1-Anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose monohydrate crystals (200 mg) and sodium acetate (40 mg) were dissolved in methanol (1 mL) at 80°C. After the solution was cooled to room temperature, isopropanol (2 mL) was added thereto. The solvent (ca. 2 ml) was removed by evaporation under reduced pressure. To this was added a seed crystal of the title co-crystal and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with isopropanol (4 ml) and dried to give the title co-crystal (melting point: 162°C). By H1 NMR analysis of the resulting co-crystal in (CD3)2SO, the ratio of the title compound and sodium acetate in the co-crystal was confirmed to be 1:1, which was calculated based on the ratio of integration of the proton peaks in ethyl CH3 of the compound (81.12-1.16 ppm (3H, t)) and in sodium acetate CH3 (81.56 ppm (3H, s)).

The seed crystal used in the preparation was obtained by the following procedure. 1,1-Anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose monohydrate crystals (8 mg) and sodium acetate (2 mg) were dissolved in methanol (0.1 ml) at 80°C. The solvent was completely evaporated from solution at 80°C to give the desired crystalline material.

Melting point measurement conditions:

Analysis Method: Differential Scanning Calorimetry (DSC)

Device: DSC6200R (SII NanoTechnology Inc.)

Sweep rate: 10°C /min

Scan range: 30 to 210°C

Sample amount: 3 to 4 mg

[Example 9] Preparation of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose co-crystal with potassium acetate

1,1-Anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose monohydrate crystals (200 mg) and potassium acetate (48 mg) were dissolved in methanol (1 mL) at 80°C. After the solution was cooled to room temperature, isopropanol (2 mL) was added thereto. The solvent (ca. 2 ml) was removed by evaporation under reduced pressure. To this was added a seed crystal of the title co-crystal and the mixture was stirred at room temperature overnight. Precipitated crystals were collected by filtration, washed with isopropanol (4 ml) and dried to give the title co-crystal (melting point: 176°C). By H1 NMR analysis of the resulting co-crystal in (CD3)2SO, the ratio of the title compound and potassium acetate in the co-crystal was confirmed to be 1:1, which was calculated based on the ratio of integration of the proton peaks in ethyl CH3 of the compound (81.13-1.16 ppm (3H, t)) and in potassium acetate CH3 (81.53 ppm (3H, s)).

The seed crystal used in the preparation was obtained by the following procedure. 1,1-Anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-p-D-glucopyranose monohydrate crystals (8 mg) and potassium acetate (2 mg) were dissolved in methanol (0.1 ml) at 80°C. The solvent was completely evaporated from solution at 80°C to give the desired crystal. The melting point was measured under the same conditions as in Example 7. [Test Example 1] Measurement of adsorption isotherm of water

The water adsorption isotherm for the monohydrate crystal of a compound represented by Formula (XI) was measured:

[Formula 31]

by using a dynamic water absorption isotherm measuring device: DVS-1 (Surface Measurement Systems) as follows.

The crushed monohydrate crystal of the compound was accurately weighed as a measurement sample (approx. 10 mg, water content: 4.5%) and placed in a sample pan. An empty sample pan was used as a control sample. The measurement sample and the control sample were placed in the device. At a constant temperature (around 25°C), the relative humidity (RH) was varied to 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% and 0% in a row, and the weight change of the measurement sample was measured. The measurement results are shown in Figure 1. The results indicate that the compound represented by Formula (XI) stably exists as a monohydrate in a relative humidity range of 10% to 90%.

[Test Example 2] Monohydrate Crystal Storage Stability Test

A storage stability test was carried out for monohydrate crystals and an amorphous form of the compound of Formula (XI). The monohydrate crystal of the compound of Formula (XI) was prepared according to the procedure of Example 1, Step 7. The amorphous form of the compound of Formula (XI) was obtained by the following procedure. The compound monohydrate crystal (15 g) was melted by heating on a hot stage and allowed to cool to room temperature in a desiccator with humidity control (25°C/dry). The resulting solid was ground in a mortar to provide a sample which was used in amorphous form. The samples were stored in thermostatic chambers at 25°C or 40°C, and the purity of each of the samples was observed after 1 month, 3 months and 6 months.

Purity was determined in the following procedure. A portion of each of the samples (approx. 6 mg) was accurately weighed and dissolved in a mixture of water and methanol (1:1) to obtain 10 ml accurately. The resulting solutions were used as sample solutions, and a portion (10 ^L) of each of the sample solutions was subjected to HPLC analysis. A total amount of impurities was calculated according to the following formula.

[Formula 32]

Total amount of impurities (%) =

Sum of areas of the peaks of each of the impurities

(Peak area of the compound of formula (XI)) (Sum of the peak areas of each of the impurities)

HPLC measurement conditions

Device: 2695 Separations Module (manufactured by Waters), 2487 Dual A Absorbance Detector (manufactured by Waters), or 996 Photodiode Array Detector (manufactured by Waters)

Column: YMC-Pack ODS-AM AM-302-3, 4.6 mm I.D. *15 cm, particle size 3 ^m (manufactured by YMC) Mobile phase: Eluent A = methanol, Eluent B = water

Gradient operation: Eluent A: 55% (15 min), Eluent A: 55% to 100% (10 min), 100% (5 min) Flow rate: 1.0 ml/min

Detection wavelength: 220nm

Sample cooler temperature: 5°C

Period to measure the peak area: 30 minutes after injection

The results are shown in Table 2. At both 25°C and 40°C, the total amounts of impurities in the amorphous form increased as a function of time. On the other hand, the total amounts of impurities in the monohydrate crystal remained almost constant for 6 months.

Table 2

[Test Example 3] Sodium acetate co-crystal storage stability test

A storage stability test was carried out for the co-crystal of the compound of Formula (XI) with sodium acetate according to the procedure of Test Example 2. The co-crystal of the compound of Formula (XI) with acetate sodium was prepared according to the procedure of Example 5. The samples were stored in thermostatic chambers at 25°C or 40°C, and the purity of each of the samples was observed after 1 month and 3 months. The measurement results were compared with those of the amorphous form obtained in Test Example 2.

The results are shown in Table 3. At both 25°C and 40°C, the total amounts of impurities in the amorphous form increased as a function of time. On the other hand, the total amounts of impurities in the co-crystal with sodium acetate remained almost constant for 3 months.

Table 3

[Test Example 4] Potassium acetate co-crystal storage stability test

A storage stability test was carried out for the co-crystal of the compound of Formula (XI) with potassium acetate according to the procedure of Test Example 2. The co-crystal of the compound of Formula (XI) with acetate potassium was prepared according to the procedure of Example 6. The samples were stored in thermostatic chambers at 25°C or 40°C, and the purity of each of the samples was observed after 1 month and 3 months. The measurement results were compared with those of the amorphous form obtained in Test Example 2.

The results are shown in Table 4. At both 25°C and 40°C, the total amounts of impurities in the amorphous form increased as a function of time. On the other hand, the total amounts of impurities in the co-crystal with potassium acetate remained almost constant for 3 months.

Table 4

[Test Example 5] Powder X-ray diffraction measurement

X-ray powder diffraction was measured for the monohydrate and amorphous form of the compound of Formula (XI) and for the co-crystals of the compound of Formula (XI) with sodium acetate and potassium acetate. The measurement conditions are shown below.

Measurement conditions for monohydrate (Condition 1)

Equipment: RINT 1100 (Rigaku Corporation)

Cathode: Cu

Tube voltage: 40kV

Tube current: 40mA

Sweep rate: 2,000 degrees/min

Sampling range: 0.020°

Divergence slit: 1°

Scattering slit: 1°

Receiving slit: 0.15mm

Sweep Range: 3 to 35°

Measurement conditions for monohydrate (Condition 2)

Team: X'Pert MPD (PANalytical)

Cathode: Cu

Tube voltage: 45kV

Tube current: 40mA

Sweep mode: continuous sweep

Step Width: 0.017

Sweep axis: 20

Sampling time per step: 30 sec.

Sweep Range: 2 to 35°

Measurement conditions for the amorphous form

Equipment: RINT 1100 (Rigaku Corporation)

Cathode: Cu

Tube voltage: 40kV

Tube current: 20mA

Sweep speed: 2,000 degrees/min

Sampling range: 0.020°

Divergence slit: 1°

Scattering slit: 1°

Receiving slit: 0.15mm

Sweep Range: 2 to 35°

Measurement conditions for co-crystals with sodium acetate and potassium acetate

Team: X'Pert MPD (PANalytical)

Cathode: Cu

Tube voltage: 45kV

Tube current: 40mA

Sweep speed: 1,000 degrees/min

Sampling range: 0.050°

Divergence gap: 0.25°

Scattering slit: 0.25°

Receiving slit: 0.2mm

Sweep Range: 3 to 35°

The result of the monohydrate was shown in Figure 2. Peaks were observed at diffraction angles (20) of approximately 3.5°, 6.9°, 10.4°, 13.8°, 16.0°, 17, 2°, 18.4°, 20.8°, 21.4° and 24.4°. The result of the co-crystal with sodium acetate is shown in Figure 4. Peaks were observed at diffraction angles (20) of approximately 4.9°, 8.7°, 9.3°, 11.9°, 12 .9°, 14.7°, 16.0°, 17.1°, 17.7°, 19.6°, 21.6° and 22.0°. The result of the co-crystal with potassium acetate is shown in Figure 5. Peaks were observed at diffraction angles (20) of approximately 5.0°, 10.0°, 10.4°, 12.4°, 14 .5°, 15.1°, 19.0°, 20.1°, 21.4° and 25.2°.

Claims (13)

1. A crystal of a compound represented by Formula (XI):

What is it i) a monohydrate, ii) a co-crystal with sodium acetate, or iii) a co-crystal with potassium acetate. 2. The crystal of a compound represented by Formula (XI) according to claim 1, which is a monohydrate. 3. The crystal of a compound represented by Formula (XI) according to claim 2, having peaks at diffraction angles (20) of approximately 3.5°, 6.9° and 13.8° in the diffraction pattern X-ray powder. 4. The crystal of a compound represented by Formula (XI) according to claim 2, having peaks at diffraction angles (20) of about 3.5°, 6.9°, 13.8°, 16.0° , 17.2° and 18.4° in the X-ray powder diffraction pattern. 5. The crystal of a compound represented by Formula (XI) according to claim 2, having peaks at diffraction angles (20) of about 3.5°, 6.9°, 10.4°, 13.8° , 16.0°, 17.2°, 18.4°, 20.8°, 21.4° and 24.4° in the X-ray powder diffraction pattern. 6. The crystal of a compound represented by Formula (XI) according to claim 1, which is a co-crystal with sodium acetate. 7. The crystal of a compound represented by Formula (XI) according to claim 6, having peaks at diffraction angles (20) of about 4.9°, 14.7°, 16.0°, 17.1° and 19.6° in the X-ray powder diffraction pattern. 8. The crystal of a compound represented by Formula (XI) according to claim 6, having peaks at diffraction angles (20) of about 4.9°, 8.7°, 9.3°, 11.9° , 12.9°, 14.7°, 16.0°, 17.1°, 17.7°, 19.6°, 21.6° and 22.0° in the powder X-ray diffraction pattern . 9. The crystal of a compound represented by Formula (XI) according to claim 1, which is a co-crystal with potassium acetate. 10. The crystal of a compound represented by Formula (XI) according to claim 9, having peaks at diffraction angles (20) of about 5.0°, 15.1°, 19.0°, 20.1° and 25.2° in the X-ray powder diffraction pattern. 11. The crystal of a compound represented by Formula (XI) according to claim 9, having peaks at diffraction angles (20) of about 5.0°, 10.0°, 10.4°, 12.4° , 14.5°, 15.1°, 19.0°, 20.1°, 21.4° and 25.2° in the X-ray powder diffraction pattern. 12. A process for preparing the crystal of a compound as defined in any of claims 1 to 11, wherein the compound is represented by Formula (XI):

wherein the process comprises Step d): converting a compound of Formula (XI) to a compound of Formula (Xc):

where P7 is a hydroxy protecting group; Step e): crystallize the compound of Formula (Xc) and purify the compound by recrystallization; Step f): Removing (a) the protecting group(s) from a compound of Formula (Xc) to provide a compound of Formula (XI) of high purity and crystallizing the resulting compound to provide the crystal of Formula (XI). 13. The process according to claim 12, wherein P7 is selected from t-butylcarbonyl and methoxycarbonyl.